The Trifunctional Antibody Ertumaxomab Destroys Tumor Cells That Express Low Levels of Human Epidermal Growth Factor Receptor 2

Abstract

Human epidermal growth factor receptor 2 (HER2/neu) is an important target for the treatment of the breast cancers in which it is overexpressed. However, no approved anti-HER2/ neu therapy is available for the majority of breast cancer patients, who express HER2/neu at low levels (with scores of 1+ or 2+/fluorescence in situ hybridization-negative). The trifunctional antibody ertumaxomab targets HER2/neu, CD3, and activating Fc; receptors. In presence of ertumaxomab, tri-cell complexes consisting of tumor cells, T cells, and accessory cells form to cause tumor cell lysis. In a phase I trial with metastatic breast cancer patients, ertumaxomab could be applied safely and resulted in radiographically confirmed clinical responses. In this study, we compare ertumaxomaband trastuzumab-mediated killing of cancer cell lines that express HER2/neu at low and high levels. Under optimal conditions for trastuzumab-mediated destruction of HER2/ neu-overexpressing cells, only ertumaxomab was able to mediate the elimination of tumor cell lines that express HER2/neu at low levels (1+). Ertumaxomab-mediated activity was accompanied by a Th1-based cytokine release, a unique mode of action of trifunctional antibodies. Competitive binding studies with trastuzumab and 520C9 mapped the binding site of ertumaxomab to the extracellular regions II and III of the HER2/neu ectodomain. This site is distinct from the binding site of trastuzumab, so that HER2/neu-expressing tumor cells can be eliminated by ertumaxomab in the presence of high amounts of trastuzumab. The ability of ertumaxomab to induce cytotoxicity against various tumor cell lines, including those with low HER2/neu antigen density, may provide a novel therapeutic option for breast cancer patients who are not eligible for trastuzumab treatment.

CODV-Ig, a universal bispecific tetravalent and multifunctional immunoglobulin format for medical applications

“…3,38,40,[72][73][74][75] The circular self-contained CODV architecture with its voluminous Fab region could raise the concern that binding of FcRs or hexamerization which potentiates complement activation might be perturbed. 40,51,76 Also, both, binding of surface antigens on target cells with concomitant FcgR engagement on immune effector cells and assembly of the complement components on antigen-bound CODV-Ig are subjected to 3D constraints that one might imagine incompatible with CODV architecture.…”

Efficient generation of stable bispecific IgG1 by controlled Fab-arm exchange

“…Human epidermal growth factor receptor 2 (HER2) is a member of the EGFR family and represents a clinically wellvalidated target for antibody therapy (30). Besides naked (31,32) and drug-conjugated (33) antibody approaches, HER2 is also being evaluated in dual-targeting strategies, involving (re)targeting of CD3-positive T cells to HER2-positive tumors by means of bsAbs (34,35). Here we evaluated the in vitro and in vivo efficacy of cFAE-derived bsIgG1-N297Q-CD3×HER2 169 (Table S1).…”

Identification and Validation of Targets for Cancer Immunotherapy: From the Bench-to-Bedside

“…Assays tend to reflect the immunotherapy strategy employed with the efficacy of antibody therapies being measured by tumour destruction, ertumaxomab destroys tumour cells expressing HER2/neu [128], bispecific antibodies represent a new class of anticancer therapeutics [129] and antibody-targeted delivery of a vaccine can improve tumour cell killing [130].…”